Project Summary In the past decade, little improvement has been made in the survival of glioblastoma multiforme (GBM) patients. Although mechanisms underlying GBM remain poorly understood, it is known that the interaction of tumor cells with inflammatory tumor microenvironment promotes cancer progression. Further, extensive inflammation is a key hallmark of GBM. NF-kB proteins are most known for their role in immune and inflammatory responses, however they also control cell proliferation, differentiation, and apoptosis. Not surprisingly, aberrant NF-kB activity has also been implicated in oncogenesis. Recently a novel ?RelB-canonical? pathway of NF-kB signaling that involves RelB/p50 dimers has been found to be active in dendritic cells. Intriguingly, our preliminary data indicate that a proinflammatory cytokine, interleukin-1? (IL-1), may support GBM progression through this RelB- canonical pathway by inducing expression of a set of RelB-dependent genes. We also discovered that IL-1 induces RelB phosphorylation; however, it remains to be determined whether this phosphorylation facilitates RelB-canonical signaling, thus driving GBM progression. We hypothesize that inflammation-induced phosphorylation of RelB promotes RelB-canonical signaling and activates a gene expression program that supports GBM progression. To test this we propose the following aims: Aim 1: Establish the role of RelB phosphorylation in its activation by IL-1 Aim 2: Evaluate the role of RelB phosphorylation in GBM Aim 3: Determine the role of RelB in GBM development and progression in vivo Completion of these aims will establish whether RelB phosphorylation promotes RelB-canonical signaling to support GBM progression. These studies could pave the way for more specific and effective GBM therapies.